RT Journal Article
SR Electronic
T1 Transcription-driven cohesin repositioning rewires chromatin loops in cellular senescence
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 823831
DO 10.1101/823831
A1 Ioana Olan
A1 Aled J. Parry
A1 Stefan Schoenfelder
A1 Masako Narita
A1 Yoko Ito
A1 Adelyne S.L. Chan
A1 Guy St.C. Slater
A1 Dóra Bihary
A1 Masashige Bando
A1 Katsuhiko Shirahige
A1 Hiroshi Kimura
A1 Shamith A. Samarajiwa
A1 Peter Fraser
A1 Masashi Narita
YR 2019
UL http://biorxiv.org/content/early/2019/10/30/823831.abstract
AB Senescence is a phenotypic state of stable proliferative arrest, typically occurring in lineage-committed cells and triggered by various stimuli. It is generally accompanied by activation of a secretory program (senescence-associated secretory phenotype, SASP), which modulates both local (tissue microenvironment) and systemic (ageing) homeostasis1,2. Enhancer-promoter interactions play a key role in gene regulation3–5, facilitated by chromatin loops, mostly formed via CCCTC binding factor (CTCF) and cohesin tethering6–8. The three-dimensional chromatin structure of senescent cells has been characterised9–11 mostly in terms of macro-domain structures, but its relevance in gene expression remains elusive. Here, we use Hi-C and capture Hi-C12,13 to show that oncogenic HRAS-induced senescence (RIS) in human diploid fibroblasts (HDFs) is accompanied by extensive enhancer-promoter rewiring, which is closely connected with dynamic cohesin binding to the genome. We find de novo cohesin peaks at the 3’ end of a subset of active genes, reminiscent of the transcription-driven ‘cohesin islands’ recently discovered in mouse embryonic fibroblasts deficient in both CTCF and the cohesin release factor Wings apart-like (Wapl)14. RIS de novo cohesin peaks are also transcription-dependent and enriched for SASP genes, as exemplified by IL1B, where de novo cohesin binding is involved in new loop formation. Cytokine induction is associated with similar cohesin islands appearance and enhancer-promoter rewiring during the terminal differentiation of monocytes to macrophages15, but not upon acute TNFα treatment of HDFs16. These results suggest that RIS represents a fate-determined process in which gene expression is regulated beyond the cell type specific 3D chromatin framework, in part through cohesin redistribution.